Lewis acid catalyzed cascade reaction to carbazoles and naphthalenes via dehydrative [3 + 3]-annulation

Article abstract of DOI:10.1021/ol501605h

A novel Lewis acid catalyzed dehydrative [3 + 3]-annulation of readily available benzylic alcohols and propargylic alcohols was developed to give polysubstituted carbazoles and naphthalenes in moderate to good yields with water as the only byproduct. The

Full text of DOI:10.1021/ol501605h

Letter
pubs.acs.org/OrgLett
Lewis Acid Catalyzed Cascade Reaction to Carbazoles and
Naphthalenes via Dehydrative [3 + 3]-Annulation
Shaoyin Wang,†,‡ Zhuo Chai,† Yun Wei,† Xiancui Zhu,† Shuangliu Zhou,† and Shaowu Wang*,†,§
†The Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, Institute
of Organic Chemistry, School of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, P. R. China
‡Department of Chemistry, Wannan Medical College, Wuhu, Anhui 241002, P. R. China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: A novel Lewis acid catalyzed dehydrative [3 +
3]-annulation of readily available benzylic alcohols and
propargylic alcohols was developed to give polysubstituted
carbazoles and naphthalenes in moderate to good yields with
water as the only byproduct. The reaction was presumed to
proceed via a cascade process involving Friedel−Crafts-type
allenylation, 1,5-hydride shift, 6π-eletrocyclization, and Wag-
ner−Meerwein rearrangement.
arbazoles are important scaffolds present in numerous
Cascade reaction systems enable the construction of complex
molecules from relatively simple and easily available starting
materials with excellent atom- and step-economy.9 Recently,
our group has been interested in the development of cascade
processes using simple electron-rich benzylic alcohols as a
versatile three-carbon synthon for the construction of useful
cyclic structures, such as tetrahydro-β-carbolines and tetrahy-
droisoquinolines.10 This type of process involves direct
dehydrative couplings between a C−OH bond and a C−H
bond to construct new C−C bonds with water as the only
byproduct, and therefore, it has been recognized as an
environmentally benign process and has prompted significant
research interest recently.11 In this context, we envisaged that 2-
indolyl methanols and propargylic alcohols would be two three-
carbon building blocks for the construction of carbazoles in a [3
+ 3]-annulation manner (Scheme 1). We report herein the
details of this research.
C
biologically and pharmaceutically active compounds.1 For
example, complex alkaloids tubingensin A and B have shown
antiviral and anticancer activity as well as potent activities
against agriculturally important pests;2 clausenine and clausenol
have shown antibiotic activities;3 and P7C3 and its analogues
have shown promising neuroprotective properties for drug
discovery in rodent models of Parkinson’s disease, age-related
cognitive decline, amyotrophic lateral sclerosis, and traumatic
brain injury (Figure 1).4 Moreover, carbazoles are also widely
The reaction of 1H-indole-2-methanol 1a and propargylic
alcohol 2a was selected as a model reaction for optimization of
reaction conditions (Table 1). Using 1,2-dichloroethane (1,2-
DCE) as solvent, four different rare-earth metal triflates were
screened, and Yb(OTf)3 was found to be the most efficient
catalyst for this reaction (Table 1, entries 2−5). No reaction
occurred in the absence of the catalyst or when the reaction was
performed at room temperature (Table 1, entries 1 and 6).
Changing the solvent to DCM, toluene, DMF, 1,4-dioxane, or
THF gave inferior results (Table 1, entries 7−10). Further
screen of catalyst loading amount revealed that 10 mol % was
Figure 1. Representative carbazole-containing natural products.
used in photorefractive materials and organic dyes for solar cells
and have found applications in the design of single-molecule
circuits and sensors.5 Consequently, a large number of
procedures have been developed with varied degrees of success
for the construction of this highly useful structure.6−8 However,
current methods more or less suffer from limited substrate
scope, complicated catalyst or noble metal catalyst systems,
not-easily accessible starting materials, and/or multistep
manipulations. Therefore, there is still great room for the
development of a simple and efficient method for the syntheses
of structurally diverse carbazoles.
Received: June 4, 2014
© XXXX American Chemical Society
A
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Letter
a
Scheme 1. Lewis Acid Catalyzed Dehydrative [3 + 3]-
Annulation Path to Useful Heterocycles
Table 2. Syntheses of Carbazoles 3
a
Table 1. Screening of Reaction Conditions
b
entry
catalyst (mol %)
solvent
time (h)
yield (%)
1
2
3
4
5
no catalyst
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
toluene
24
16
16
24
16
18
18
24
18
18
18
18
0
43
55
50
60
nr
25
0
Sc(OTf)3 (10)
Y(OTf)3 (10)
La(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (5)
Yb(OTf)3 (20)
c
6
d
7
d
8
d
DMF
9
1,4-dioxane
THF
44
56
55
59
10
11
12
1,2-DCE
1,2-DCE
a
b
d
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), solvent (5 mL).
Yield of the isolated pure product. Reaction was run at 25 °C.
Reaction was run at 90 °C.
c
a
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), Yb(OTf)3 (0.05
b
c
mmol), DCE (5 mL), 24 h. Yield of the isolated product. THF (5
mL) was used as solvent
optimal for the reaction, while lower (5 mol %) or higher (20
mol %) all led to reduced yields (Table 1, entries 11 and 12). It
is worth mentioning that the reaction is tolerant of moisture
and air and could be performed in commercial solvents under
open air.
more susceptible to other side reactions, as unidentified
byproducts were observed in these cases. However, substrate
1c having the electron-withdrawing substituent at the 4-
position of the indole ring gave diminished yield (Table 2, entry
12). N-Substituted substrates (R2 = methyl or propargyl) were
also suitable for the reaction to produce the corresponding
products in moderate yields by using THF as solvent (Table 2,
entries 15 and 16). The structures of the products 3a and 3i
were additionally confirmed by X-ray crystallographic analyses
(see Supporting Information for details).
We then examined the reactivity of 6 and 8, two sulfonamide
analogues of 1-H-indole-2-methanol 1a, under the same
reaction conditions (Scheme 2). Not surprisingly, the same
carbazole products 3h and 3o could be obtained with yields
comparable to that obtained with 1a. More importantly, in
addition to the desired products, we isolated compound 7 (44%
yield) and compound 9 (93% yield) when the two reactions
were interjected at 8 and 1 h, respectively. These two
compounds could be converted to the final products 3h and
3o under the same reaction conditions. Although attempts to
isolate similar intermediates in the reactions of other indole-2-
methanols failed, these results suggest that both 7 and 9 might
be intermediates in this type of cascade process and thus
provide important clues to the mechanism of the reaction.
With the optimized reaction conditions in hand, the scope of
the reaction was then examined with a series of indole-2-
methanols 1 and propargylic alcohols 2 (Table 2). First, a series
of substituted 2 were reacted with 1a to examine the
substituent effect (Table 2, entries 1−8). In general, propargylic
alcohols 2 bearing electron-donating substituents on either of
the two aryl groups (R3, R4) provided higher yields than those
with electron-withdrawing ones. Such a phenomenon suggests
the intermediacy of carbocation species in this reaction.
Notably, when the propargylic alcohol 2i with two different
aryl groups (R4) was employed, the electron-rich aryl group
migrated predominantly to give the product 3i (Table 2, entry
9). Moreover, when 9-fluorenyl-substituted 2l was subjected to
the reaction conditions, a polycyclic heteroaromatic product 3j
could be formed in an acceptable 31% yield (Table 2, entry 10).
Differently substituted 2-indolyl methanols 1 were then
examined in the reaction (Table 2, entries 11−16). While the
presence of an electron-donating substituent on the benzene
ring of indole seemed to be detrimental to the reaction (Table
2, entry 11 vs entry 7), the presence of an electron-withdrawing
one seemed favored (Table 2, entries 13, 14 vs entry 1). This
might be because the presence of electron-donating sub-
stituents would render the corresponding indole substrates
B
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Letter
On the basis of the above experimental results, a plausible
mechanism for the present cascade reaction was proposed
(Scheme 3). First, propargylic alcohol 2a is converted to the
Scheme 2. Reaction of Indole-2-sulfonamides with
Propargylic Alcohols
Scheme 3. Possible Mechanism for the Dehydrative [3 + 3]-
Annulation
To further extend the scope of the current reaction, we then
tested electron-rich primary benzylic alcohols 4 as substrates in
lieu of indole-2-methanols 1. To our delight, under very similar
reaction conditions, the reaction of 4 with different propargylic
alcohols 2 could provide various substituted naphthalene
products in moderate to good yields (Table 3). Compared to
a
Table 3. Syntheses of Naphthalenes 5
allenic carbocation I via Meyer−Schuster rearrangement,12
which would then undergo Friedel−Crafts-type reaction with 1f
to form the allene intermediate II. The isolation of the
compound 9 in Scheme 2 is in support of this assumption.
Then allene II would be transformed to alcohol III via [1,5]-H
shift, followed by 6π-eletrocyclization to provide intermediate
IV, which is also supported by the isolation of the compound 7
in Scheme 2. The intermediate IV would undergo Wagner−
Meerwein rearrangement following the loss of the hydroxyl
group with assistance of the catalyst, and subsequent
aromatization would deliver the final product.
b
entry
2, R3/R4
2a, Ph/Ph
5
yield
1
5a
5b
5c
5d
5e
5f
74
71
64
80
79
73
82
66
65
56
71
2
2b, 4-MeC6H4/Ph
3
2c, 4-MeOC6H4/Ph
2d, 3-ClC6H4/Ph
4
To gain more support for the proposed reaction mechanism,
two deuterium-labeling experiments were performed (Scheme
4). The reaction between deuterated N-methylindole-2-
5
2e, 4-ClC6H4/Ph
6
2f, Ph/4-MeC6H4
7
2h, Ph/4-ClC6H4
5g
5h
5i
8
2j, Ph/9-fluorenyl
Scheme 4. Deuterium-Labeling Reaction
9
2k, 4-MeC6H4/9-fluorenyl
2l, 4-MeOC6H4/9-fluorenyl
2a, 4-ClC6H4/9-fluorenyl
10
11
5j
5k
a
Reaction conditions: 4 (0.5 mmol), 2 (0.5 mmol), Yb(OTf)3 (0.05
b
mmol), THF (5 mL), 24 h. Yield of the isolated product.
indole-2-methanols 1, the benzylic alcohols 4 were more stable
and less susceptible to side reactions under the reaction
conditions to give generally higher yields, although they are less
reactive as nucleophile and a longer reaction time (24 h) was
required. Moreover, compared to the reaction results of 2 with
indole-2-methanols 1, the electronic nature of the substituents
on the R4 group of propargylic alcohols 2 demonstrated
reversed influence on the reaction: electron-withdrawing
substituents were more favorable than electron-donating ones
(Table 3, entries 1−7). This might be ascribed to the higher
electrophilicity of the corresponding cationic species formed
from 2 under Lewis acid catalysis in the presence of electron-
withdrawing substituents, which is favored in the reaction with
the less nucleophilic benzylic alcohol 4. Notably, polyconju-
gated aromatic compounds 5h−5k were also obtained in good
yields when 9-fluorenyl propargylic alcohols were used (Table
3, entries 8−11). The structure of the product 5i was
unambiguously confirmed by X-ray crystallographic analysis.
methanol 1f-d2 and propargylic alcohol 2g gave the desired
product 3o-d with 84% deuterium at the 3-position (eq 1). The
failure of 100% deuterium transfer from 1f-d2 to 3o-d was
presumed to be due to the presence of the proton sources in
the system including the two alcohol hydroxyl groups in the
substrates, the proton released after the Friedel−Crafts-type
C
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6π-eletrocyclization, and Wagner−Meerwein rearrangement.
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ASSOCIATED CONTENT
* Supporting Information
Spectral and X-ray data, experimental procedures; CIF files for
3a, 3i, and 5h; 1H and 13C NMR copies of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: swwang@mail.ahnu.edu.cn.
Notes
(12) (a) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971, 71,
429. (b) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21372010, 21072004, 21202001), the
National Basic Research Program of China (2012CB821604),
the Science Foundation for Postdoctoral Scientists of Anhui
Province, the Natural Science Foundation of Anhui Province
(1308085QB25), and the Research Fund for the Doctoral
Program of Wannan Medical College.
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